1. health and fitness
2. disease

Dermatology 2003;206:37–53
DOI: 10.1159/000067821
Update and Future of Systemic Acne
Treatment
Christos C. Zouboulis a Jaime Piquero-Martin b
a Department
b Institute
of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin, Berlin, Germany;
of Biomedicine, Hospital Vargas, Central University of Venezuela, Caracas, Venezuela
Key Words
Acne W Therapy W Update W Future W Review
Abstract
Systemic treatment is required in patients with moderate-to-severe acne, especially when acne scars start to
occur. Antibiotics with anti-inflammatory properties,
such as tetracyclines (oxytetracycline, tetracycline chloride, doxycycline, minocycline and limecycline) and
macrolide antibiotics (erythromycin and azithromycin)
are the agents of choice for papulopustular acne, even
though the emerging resistant bacterial strains are minimizing their effect, especially regarding erythromycin.
Systemic antibiotics should be administered during a
period of 8–12 weeks. In severe papulopustular and in
nodulocystic/conglobate acne, oral isotretinoin is the
treatment of choice. Hormonal treatment represents an
alternative regimen in female acne, whereas it is mandatory in resistant, severe pubertal or post-adolescent
forms of the disease. Compounds with anti-androgenic
properties include estrogens combined with progestins,
such as ethinyl estradiol with cyproterone acetate, chlormadinone acetate, desogestrel, drospirenone, levonogestrel, norethindrone acetate, norgestimate, and other
anti-androgens directly blocking the androgen receptor
(flutamide) or inhibiting androgen activity at various levels, corticosteroids, spironolactone, cimetidine, and ketoconazole. After 3 months of treatment control of
ABC
© 2003 S. Karger AG, Basel
1018–8665/03/2061–0037$19.50/0
Fax + 41 61 306 12 34
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seborrhea and acne can be obtained. Low-dose corticosteroids (prednisone, prednisolone, or dexamethasone)
are indicated in patients with adrenal hyperandrogenism
or acne fulminans. New developments and future trends
represent low-dose long-term isotretinoin regimens,
new isotretinoin formulations (micronized isotretinoin),
isotretinoin metabolites, combination treatments to reduce toxicity, insulin-sensitizing agents, 5·-reductase
type 1 inhibitors, antisense oligonucleotide molecules,
and, especially, new anti-inflammatory agents, such as
lipoxygenase inhibitors.
Copyright © 2003 S. Karger AG, Basel
Acne is a disorder of the pilosebaceous units located on
the face, chest and back. It is an almost universal disease,
occurring in all races, predominantly among adolescents
[1–4]. Epidemiological studies have shown that about 70–
87% of the adolescents experience acne lesions [5, 6]. The
disease exhibits a peak incidence at 15–18 years of age.
Spontaneous regression occurs in the majority of the
patients after puberty, but in 10% of them acne persists
over the age of 25 years and can last up to the 4th decade of
life, and even up to the 6th decade of life in some cases.
As many as 15–30% of patients with acne need medical treatment because of the severity and/or persistence of
their disease. In the years 1996–1998, more than 6 million
visits per year to office-based physicians with acne as the
principal reason have been registered in the USA; the
Prof. Dr. Christos C. Zouboulis
Department of Dermatology
University Medical Center Benjamin Franklin, The Free University of Berlin
Fabeckstrasse 60–62, D–14195 Berlin (Germany)
Tel. +49 30 8445 6910, Fax +49 30 8445 6908, E-Mail [email protected]
Table 1. Simplified acne severity grading for the therapeutic decision
Severity
grade
Comedones
Papules/
pustules
Small nodules,
cysts, fistules
Nodules
Inflammation
Scar
formation
Mild
Moderate
Severe
Very severe
few
numerous
numerous
fistule-comedones
n or few
few to many
very numerous
very numerous
n
n or few
many
many
n
n
n or few
few to many,
deeply located
n
marked
strong
very strong
n
n
present
present
patients received 6.5 million new prescriptions per year
for systemic anti-acne drugs (antibiotics or isotretinoin)
with a total cost likely to exceed USD 1 billion [7]. The
different age ranges and the varying clinical pictures
require better knowledge of the pathogenesis of the disease and clinical experience for its treatment [1–5, 8],
especially since misconceptions regarding factors that exacerbate acne vulgaris not only exist in the community
but have also been registered in last year medical students
in an Australian study [9]. Several factors contribute to
the pathogenesis of acne, among them increased sebaceous gland activity with hyperseborrhea [10], abnormal
follicular differentiation and increased cornification [11],
bacterial hypercolonization [12] as well as inflammation
and immunological host reaction [13] are considered to be
the major ones. Each of these factors provides a potential
target for treatment. Genetic investigations have provided ambiguous proof for hereditary factors [14]; irregularities of the menstrual cycle, pregnancy, etc., have some
influence on the acne course in females, and nutritional
factors are accused to modify acne in some patients.
Weather including ultraviolet light and other environmental factors may occasionally play a role. Several drugs
can induce acne or acneiform lesions [3]. Psychological
factors and stress have still no proven influence on the
pathogenesis of acne but are often involved in its course.
Recently, neuropeptides were reported to regulate the
activity of the pilosebaceous unit [15, 16]. At last, acneiform eruptions can complicate the diagnosis.
Treatment of Acne: General Considerations
The exact classification and grading of acne is a fundamental requirement for the decision of the therapeutic
regimen [1–4, 17–19]. In addition, acne at puberty needs
subsequent prophylactic medication and care over several
years after clinical healing. Infantile and pediatric acne,
38
Dermatology 2003;206:37–53
androgenization signs in female patients with acne tarda
[20, 21] or patients with signs of acne inversa may necessitate an alternative treatment. The compliance of the
patient is an additional important parameter for the therapeutic strategy to be considered and its success. Skin type
(dark skin tends to postinflammatory hyperpigmentation)
and, especially, the tendency for scar formation play a role
in the selection of treatment [22]. Two to 7% of the
patients with acne experience a severe course associated
with considerable scarring. A severe course associated
with the presence of potential generators of physical and
psychotic scars may require a therapeutic regimen based
on systemic drugs [3, 18] (table 1).
Therapeutic Targets and Acne Drugs
Several clinical observations point to the importance
of androgens in acne [23]. Androgens play an essential
role in stimulating sebum production; androgen-insensitive subjects who lack functional androgen receptors do
not produce sebum and do not develop acne. Moreover,
systemic administration of testosterone and dehydroepiandrosterone increases the size and secretion of sebaceous glands [24–27]. Sebosuppression, i.e. suppression of
sebaceous gland hyperactivity, can classically be achieved
by systemic administration of anti-androgens or isotretinoin [19, 24–26, 28, 29] (table 2).
Abnormal keratinization of the infundibulum and the
distal part of the sebaceous duct can be directly influenced
through topical and systemic retinoids as well as through
topical application of azelaic acid [30]. A number of further drugs can also secondarily induce keratolysis over
their influence on other pathogenic factors [31]. Benzoyl
peroxide and topical and systemic antibiotics primarily
exhibit antimicrobial, but also anti-inflammatory activities [32, 33]. Various agents administered in acne treatment exhibit direct or indirect anti-inflammatory activi-
Zouboulis/Piquero-Martin
Table 2. Different action profile of
systemic anti-acne drugs on the four major
pathogenic factors of acne
Antiandrogens(s)
Isotretinoin(s)
Tetracyclines(s)
Follicular
hyperkeratosis
Seborrhea
Bacterial
Inflammation
hypercolonization
–
++
–
++
+++
–
–
(+)
++
–
++
+
+++ = Very strong, ++ = strong, + = moderate, + = indirect/weak.
ties in addition to their effects on further pathogenic factors of acne. However, solely anti-inflammatory agents
have rarely been administered [13].
Bacterial hypercolonization is not involved at the onset of acne, but it plays a role in the maintenance of the
disease [2, 3, 8]. Propionibacterium acnes (P. acnes), an
anaerobic bacterium, is a normal constituent of the cutaneous flora; however, it is virtually absent in the skin
before puberty. Sebaceous follicles turning to microcomedones provide an anaerobic, lipid-rich environment for
optimum bacterial proliferation. P. acnes produces lipases which can split triglycerides into free fatty acids.
The latter can irritate the follicular cells and may cause
hyperproliferation and/or inflammation. Topical or systemic antibiotics administered successfully in acne patients exhibit a suppressive effect on P. acnes proliferation
but also directly suppress inflammation by decreasing
neutrophil chemotaxis and down-regulating the expression of pro-inflammatory mediators and the production
of chemotactic factors [34]. The unique environment of
the pilosebaceous follicle makes lipophilic compounds
clinically more active than hydrophilic ones [35].
Inflammation in acne has been considered as secondary
to bacterial hypercolonization and, consequently, neither
has it been carefully investigated nor become the target of
treatment. The major hypothesis was that early during
development of acne lesions neutrophils accumulate
around and in the follicles through chemoattractive substances which may originate from P. acnes [1–4]. Hydrolytic enzymes and reactive oxygen species released by neutrophils promote tissue damage, facilitating the occurrence of
debris within the lumen. The latter is considered to trigger
the inflammatory cascade [36]. This hypothesis has gained
support because several anti-acne drugs have been shown
to inhibit the generation or activity of chemotactic factors
or the release of reactive oxygen species [37]. In addition,
linoleic acid, which is deficient in acne comedones, inhibits
neutrophil oxygen metabolism and phagocytosis.
Table 3. Indications for oral antibiotic therapy in acne
Systemic Acne Treatment
Dermatology 2003;206:37–53
Patients with moderate to severe acne
Patients for whom topical antibiotic therapy has failed or cannot be
tolerated
Patients with moderate acne with tendency for scarring or
substantial post-inflammatory hyperpigmentation
Patients with involvement of the shoulders, back or chest
(difficult for topical application)
Systemic Treatment
Oral Antibiotics
Oral antibiotics are indicated for several groups of
patients with inflammatory acne (table 3) [33, 38]. They
include tetracyclines (tetracyclines, doxycycline, minocycline), erythromycin, clindamycin, and cotrimoxazole (table 4). These agents improve inflammatory acne by inhibiting the growth of P. acnes; tetracyclines and erythromycin have additional anti-inflammatory properties.
Tetracyclines of the first generation (tetracycline, oxytetracycline and tetracycline chloride) are the most commonly prescribed oral antibiotics for acne. They are used
as a first-line agent because of their efficacy and low cost,
although they have generated high rates of bacterial resistance. A 6-week treatment decreases the number of inflammatory lesions by approximately 50%. They are
usually administered at a dose of 1 g/day (500 mg twice
daily) over several months and after marked clinical
improvement the dose can be reduced to 500 mg/day.
Because their absorption is inhibited in the presence of
food and dairy products, the drug must be taken preferably on an empty stomach one hour before meals with
water for an optimal absorption.
Alternatively, tetracyclines of the second generation,
namely doxycycline (initial dose of 100–200 mg/day with
39
Fig. 1. Mild acne papulopustulosa in a 24-
year-old male patient before (left) and after a
6-month treatment with doxycycline 2 !
100 mg/day and topical tretinoin 0.1%
(right).
Table 4. Oral antibiotics used in acne
treatment
Antibiotic
Usual dose
Comments
Tetracycline
250–500 mg ! 2/day
Doxycycline
Minocycline
100 mg ! 2/day
50–100 mg ! 2/day
Erythromycin
500 mg ! 2/day
Clindamycin
Cotrimoxazole
300 mg ! 3/day
160/800 mg ! 2/day
low cost
decreased absorption in presence of foods
and dairy products
may be taken with meals
expensive
may be taken with meals
safety problems
common emergence of resistant P. acnes
strains
safety problems after long-term use
second-line therapy in acne
50 mg/day as maintenance dose) (fig. 1) and minocycline
(usually 100 mg/day; 50 mg twice daily or 100 mg once
daily) are more expensive but also more lipid soluble and
better absorbed from the gastrointestinal tract. In contrast
to tetracyclines of the first generation their absorption is
not significantly limited by food, therefore, they can be
taken with meals even though it is more effective when
taken 30 min previously. Among tetracyclines, minocycline seems to induce more rapid clinical improvement as
well as greater and more persistent reduction of inflammatory lesions and facial P. acnes counts, probably because it is the most lipophilic and may become highly concentrated in the pilosebaceous unit after its oral adminis-
40
Dermatology 2003;206:37–53
tration [39]. Its major limitation occurs from currently
observed significant safety problems (table 5) [40–43].
Erythromycin at a dosage of 1 g/day can be administered as an alternative regimen. It is equally effective with
tetracycline; however, it induces higher rates of resistant
P. acnes strains and may, therefore, be more often associated with treatment failures [12]. Its intolerable gastrointestinal side effects can be minimized by using intestinesoluble preparations.
Clindamycin is very effective but has disadvantages
for long-term therapy because of the possible induction of
pseudomembranous colitis. Cotrimoxazole (trimethoprime/ sulfamethoxazole, 160 mg/800 mg twice daily) is
Zouboulis/Piquero-Martin
effective in acne, however, it is recommended to reserve
this drug for patients who responded inadequately to other antibiotics and for patients with gram-negative folliculitis.
Bacterial resistance is not rare after systemic administration of antibiotics over several months (table 5). Gastrointestinal upset under tetracycline and doxycycline
with nausea, vomiting and diarrhea and vaginal candidosis under tetracycline are probably caused through
changes in the gastrointestinal flora. Ultraviolet light sensitivity under tetracycline and doxycycline, not under
minocycline, is frequent. Painful onycholysis has been
occasionally observed under tetracycline treatment. Minocycline may cause allergic skin reaction, reversible vestibular disturbances (e.g. dizziness, vertigo, ataxia) and a
blue-grey discoloration of the skin, particularly in inflamed areas, due to a reaction with free iron. Rarely, hepatitis and reactions resembling serum sickness and lupus
erythematosus have been reported in association with oral
use of tetracyclines, particularly minocycline. The teeth
discoloration reported in children under 10 years can
rarely also occur in adults. Tetracyclines are also accused
for inducing benign intracranial hypertension which is,
however, a rare adverse event. Tetracyclines must not be
combined with systemic retinoids because the probability
for development of intracranial hypertension increases.
Since tetracyclines are contraindicated in pregnancy,
erythromycin has to be administered as an alternative
drug. Erythromycin causes the most frequent emergence
of resistant P. acnes strains. It is also responsible for intolerable gastrointestinal side effects in many patients. Clindamycin treatment of acne is almost abandoned in several
countries because of its association with pseudomembranous colitis due to intestinal colonization with Clostridium difficile. Metronidazole is then indicated in those
cases. Appearance or enhancement of a vaginal candidosis can be observed in females, which frequently settles
over the intestinal region.
Treatment with oral antibiotics should be administered for no less than 2 months but also generally not
exceed 4–6 months [44]. Maximum clinical improvement
is to be expected in the first 3–4 months; lack of improvement may indicate emergence of bacterial resistance [12].
Systemic antibiotics can be well combined with topical
preparations, especially tretinoin, azelaic acid and benzoyl peroxide [45, 46].
Table 5. Adverse events of systemic antibiotics
Adverse event
Compound
Bacterial resistance
tetracyclines 1 erythromycin
1 cotrimoxazole 1 minocyclin
clindamycin, tetracyclines
clindamycin
minocycline 1 tetracycline
minocycline
minocycline, cotrimoxazole
Gastrointestinal discomfort
Pseudomembranous colitis
Postinflam. hyperpigmentation
Vestibular disturbances
Hypersensitivity reaction
Lupus erythematosus-like
syndrome
minocycline
Interstitial nephritis/hepatic failure/
systemic eosinophilia
minocycline
Oral Isotretinoin
Oral isotretinoin is the most effective sebosuppressive
agent and has revolutionized the treatment of severe acne
[28, 47–50]. It is the only drug currently available that
affects all four pathogenic factors of acne. Like other retinoids, isotretinoin reduces comedogenesis. Moreover, it
reduces sebaceous gland size (up to 90%) by decreasing
proliferation of basal sebocytes, it suppresses sebum production in vivo and inhibits terminal sebocyte differentiation. Its stereoisomers tretinoin and alitretinoin (9-cis
retinoic acid) were found inferior to isotretinoin in sebum
suppression or acne treatment. Although not directly
affecting P. acnes, its inhibitory effect on sebum production leads to alteration of the follicular microclimate and
indirect fall of P. acnes counts reducing its ability to cause
inflammation [51].
There is still debate as to the choice of dose. Some
authors favor isotretinoin 0.5 mg/kg/day, others advocate
higher dosage of 1 mg/kg/day. Although both regimens
result to the same degree of long-term clinical improvement, relapse necessitating re-treatment occurs significantly more frequently under low-doses among patients
with severe acne [52–53]. A 6-month treatment course is
sufficient for 99% of the patients, but it has been documented that an initial dosage of 1 mg/kg/day for 3
months, then reduced to 0.5 and, if possible, to 0.2 mg/
kg/day for 3-9 additional months will optimize the therapeutic outcome. As a rule, after 2-4 weeks of treatment, a
50% reduction of the pustules can be expected. Improvement continues during the post-treatment period. Relapses may occur after a single 6-month course. A 22-30%
relapse rate was noted in patients followed for 10 years
after having received isotretinoin 1 mg/kg/day (or cumulative dose 6120 mg/kg), as compared to 39-82% with
lower dose schedules [48].
Today, a 6- to 12-month course isotretinoin 0.5–1 mg/
kg/day in most cases with severe acne, to reach a
Systemic Acne Treatment
Dermatology 2003;206:37–53
41
Fig. 2. Severe acne papulopustulosa in a 21-
year-old male patient before (left) and after a
4-month treatment with isotretinoin 0.5 mg/
kg/day (right).
Fig. 3. Acne conglobata in an 18-year-old
male patient before (left) and after a 6month treatment with isotretinoin 1 mg/kg/
day (cumulative dose 144 mg/kg) (right)
[from ref. 28].
6150 mg/kg total cumulative dose is recommended [28]
(fig. 2–4). Three to 4 weeks after administration of the
drug, an apparent flare-up may occur with increased
development of inflammatory lesions which usually do
not require modification of the oral dose and improve
spontaneously. Factors contributing to the need for longer
treatment schedules include low dose regimens (0.1–
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Dermatology 2003;206:37–53
0.5 mg/kg/day), presence of severe acne, extra-facial involvement and prolonged history of the disease. Higher
dosages are indicated particularly for severe involvement
of the chest and back [54]. Individual risk factors must be
taken into account for establishing the dosage. Indications
for optimal use are shown in table 6.
Zouboulis/Piquero-Martin
Fig. 4. Acne tarda without hormonal distur-
bances in a 44-year-old female patient before
(left) and after a 12-month treatment with
isotretinoin 0.5 mg/kg/day combined with
ethinyl estradiol 35 Ìg/day – cyproterone
acetate 2 mg/day (right).
The clinical course of isotretinoin therapy shows more
rapid improvement of inflammatory lesions as compared
to comedones. Pustules are cleared earlier than papules or
nodules, and lesions localized on the face, upper arms and
legs tend to clear more rapidly than trunk lesions [55].
Non-acne patients who have received oral isotretinoin
therapy for seborrhea do not usually experience relapse
for months or years. However, the duration of the sebostatic effect seems to be dose-dependent. Taking good tolerance into account, a dosage of 0.1–0.3 mg/kg/day over 4
weeks is sufficient to produce a sebostatic effect for at
least 8 weeks after discontinuation of treatment. Five to
10 mg/day may be sufficient as a maintenance sebosuppressive dose over several years.
In female patients contraception is required and has to
be enforced by the physician, because of the strong teratogenicity of isotretinoin [56, 57]. Isotretinoin can be well
combined with a contraceptive pill which includes a hormonal anti-androgen [28, 57].
The adverse effect profile of oral isotretinoin is closely
associated with hypervitaminosis A [28]. It includes a
characteristic dose-dependent symptomatology with mucocutaneous side effects (table 7), elevation of serum lipids (approx. 20%), hyperostosis and extra-skeletal calcification (table 9). Arthralgia and myalgia may occur in up
to 5% of individuals receiving high-dose isotretinoin. The
major toxicity of isotretinoin results, however, from its
Table 6. Indications for optimal use of systemic isotretinoin
Systemic Acne Treatment
Dermatology 2003;206:37–53
Severe acne (nodulocystica, conglobata, fulminans)
Patients with active acne and severe acne scars or potentially
possible induction of physical or psychological scars
Patients with acne papulopustulosa who despite several
conventional therapies, do not improve
Patients with acne papulopustulosa whose acne has responded well
to conventional oral treatment on two or three occasions but has
relapsed quickly after interruption of oral medication
Depressive and dysmorphobic patients
In combination with oral contraceptive treatment in women with
acne and signs of peripheral hyperandogenism
Patients with excessive seborrhea
Patients with gram-negative folliculitis
teratogenic potential associated with high rate of spontaneous abortions and life-threatening congenital malformations. Therefore, the preparation can only be administered in women in combination with a secure contraceptive treatment or technique. Contraception is urgently
recommended from 1 month before therapy, during the
entire period of treatment and up to 3 months after discontinuation of the regimen. Oral isotretinoin treatment
appears today strictly contraindicated in pregnancy, the
43
lactation period and in severe hepatic and renal dysfunction. Hyperlipidemia, diabetes mellitus and severe osteoporosis are relative contraindications. Co-medication
with vitamin A (increased toxicity), tetracyclines (cranial
hypertension) and high doses of aspirin (potentiation of
mucosal damage) should be avoided. Liver and fat values
in blood must be regularly controlled [58].
In long-term therapy (over 1–2 years), changes in the
bone system with hyperostosis, periostosis, demineralization, thinning of the bones and premature calcification of
epiphyses in adolescents have to be taken into consideration [59]. A radiograph and growth measurements are
Table 7. Mucocutaneous adverse events of
isotretinoin (% values)
Cheilitis
Dermatitis facialis
Xerosis
Dry mucosa
Conjunctivitis
Epistaxis
Itching
Epidermal atrophy
Skin fragility
Desquamation
Hair loss
Retinoid dermatitis
75–95
30–50
30–50
20–50
30
25
25
15–25
15–20
10–20
10–20
5
Table 8. Indications for optimal use of hormonal therapy in women
Acne accompanied by mild or moderate hirsutism
Inadequate response to other acne treatments
Acne that began or worsened in adulthood
Premenstrual flares of acne
Excessive facial oilness
Inflammatory acne limited to the ‘beard area’
Table 9. Adverse events of systemic
anti-acne drugs
reasonable tests before treatment of adolescents. Longterm adverse events after discontinuation of isotretinoin
are rare.
Anti-Androgens
Hormonal anti-androgenic treatment can be administered in female patients to target the pilosebaceous unit
and may inhibit sebum production by 12.5–65% (table 8)
[25–27, 60, 61]. Once the decision has been made to initiate hormonal therapy, there are various options to choose
among androgen receptor blockers and inhibitors of androgen synthesis at the levels of the ovary or the adrenal gland.
Hormonal anti-androgenic treatment for acne must be
continued for a sufficient period of time, at least 12 months
and frequently longer. It is absolutely contraindicated in
women who want to become pregnant due to the risk for
sexual organ malformation in a developing fetus.
A most effective compound is cyproterone acetate,
which belongs to the group of hydroxy-progresterones and
blocks the binding of androgens to their receptors. There
is current evidence that cyproterone acetate exhibits a
dual activity by also inhibiting the synthesis of adrenal
androgens because it inhibits the conversion of dehydroepiandrosterone to androstenedione by 3ß-hydroxysteroid dehydrogenase/¢5–4-isomerase, which mainly occurs
in the adrenal gland, and in the skin, in the sebaceous
gland. Cyproterone acetate is incorporated in a marketed
hormonal contraceptive at a dose of 2 mg in combination
with 35 Ìg ethinyl estradiol to avoid menstrual cycle problems [62–65] (fig. 5). The preparation can be used for both
contraception and treatment of acne with or without signs
of hyperandrogenism, even when serum androgen levels
are normal. It has been shown to decrease serum gonadotropin, testosterone and androstenedione, with control of
seborrhea and acne after three months treatment. In
women with abnormal androgen metabolism additional
cyproterone acetate 10–20 mg/day, and in some cases up
to 50 mg/day can be administered orally during the first
Agent
Adverse event
Isotretinoin
teratogenicity, skin and mucosal dryness, irritation,
bone changes, increase of the blood values for neutral
lipids (cholesterol, triglycerides)
edemas, thrombosis, increased appetite, weight gain,
breast tenderness, decreased libido
breast tenderness, menstrual irregularities, increased
potassium blood levels
Hormonal contraceptives
Spironolactone
44
Dermatology 2003;206:37–53
Zouboulis/Piquero-Martin
Fig. 5. Acne nodulocystica in a 20-year-old
female patient before (left) and after a
6-month treatment with ethinyl estradiol
35 Ìg/day – cyproterone acetate 2 mg/day
(right).
Fig. 6. Acne tarda with increased serum
dihydroepiandrosterone in a 31-year-old female patient before (left) and after a 2month treatment with prednisolone 5 mg/
day (right).
10 days of the menstrual cycle. Alternatively, a single i.m.
injection of 100–300 mg cyproterone acetate can be
applied at the beginning of the cycle.
There are other hormonal blockers of androgen receptors available, such as the gestagene chlormadinone acetate (2 mg) alone or in combination with 50 Ìg ethinyl
estradiol or 50 Ìg mestranol in a contraceptive pill [66].
Most oral contraceptives contain two agents, estrogen
(generally ethinyl estradiol) and a progestin. In their early
formulations, oral contraceptives included high estrogen
concentrations of over 100 Ìg which could directly suppress sebum production; low estrogen levels used currently act in the liver to increase the synthesis of sex hormonebinding globulin (SHBG). Circulating free testosterone
Systemic Acne Treatment
Dermatology 2003;206:37–53
45
levels are reduced by the increased SHBG levels, leading
to a decrease in sebum production. Oral contraceptives
inhibit the ovarian production of androgens by suppressing ovulation. This, in turn, decreases serum androgen
levels and reduces sebum production. On the other hand,
the progestins administered belong to the families of
estranes and gonanes with a variety of drugs in each class.
Some progestins can cross react with the androgen receptor or, like the progestins norgestrel and levonorgestrel,
reduce SHBG increasing free testosterone, thus leading to
increased androgenic effects and aggravating acne, hirsutism, or androgenic alopecia [67, 68]. They can also
cause changes in lipid metabolism and can increase serum
glucose, leading to glucose intolerance, as well as possibly
interfering with the beneficial effect of estrogen on the
SHBG. Hormonal contraceptives are associated with edema, thrombosis, increased appetite, weight gain, breast
tenderness and decreased libido [61].
Spironolactone, a synthetic steroid primarily acting as
aldosterone antagonist, also blocks the androgen receptor
exhibiting sufficient sebosuppression at doses 50–200 mg/
day, a 2 ! 25 mg regimen daily or at 4–22 days of cycle
being the mostly used in anti-acne therapy. It may induce,
however, cycle disturbances which can be corrected by
non-androgenic progestins [69]. Spironolactone may induce dose-dependent breast tenderness, menstrual irregularities and increased potassium blood levels [70].
Flutamide, a synthetic compound which has mainly
been administered to hirsute females, has been also shown
to be active in acne after 1–6 months of treatment at doses
of 250–500 mg/day (optimum 2 ! 250 mg/day over 6
months) [63]. The agent becomes active through first-pass
metabolism to 2-hydroxyflutamide. It inhibits binding of
5·-dihydrotestosterone to its receptor protein and nuclear
translocation of the receptor. Also, it may accelerate conversion of active androgens to inactive metabolites. Hepatic function laboratory tests should be done periodically
[71].
Among nonhormonal anti-androgens, ketoconazole
(cytochrome P-450 inhibitor and steroidogenesis enzyme
blocker) in a dose of 1200 mg/day and cimetidine (H2receptor antagonist) 5 ! 300 mg/day exhibit weak antiandrogenic activity [70].
Gonadrotropin-releasing agonists, such as buserelin,
nafarelin or leuprolide, have been used to interrupt androgen production by the adrenals and ovaries by blocking
FSH and LH liberation by the pituitary gland. These
drugs are efficacious in acne and hirsutism, and are available as injectable drugs or nasal spray [25, 67]. However,
in addition to suppressing the production of ovarian
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Dermatology 2003;206:37–53
androgens, they also suppress the production of estrogens,
thereby eliminating the function of the ovary. Thus, the
patient could develop menopausal symptoms and suffer
from hypoestrogenism. They have variable acceptance
due to the development of headaches as well as the occurrence of bone loss, due to the reduction in estrogen. They
have not been registered for the treatment of acne.
Severe Inflammatory Acne and Acne fulminans
Systemic corticosteroids can become necessary in acne
fulminans to suppress the excessive immunological reaction [54], in severe inflammatory forms of acne, and in
order to prevent or treat a severe flare of the disease in the
first 4 weeks of isotretinoin treatment. It is preferable to
administer the corticosteroids for 3–4 weeks before administration of isotretinoin [72] but a combination of isotretinoin 0.5–1 mg/kg body weight/d and prednisolone
30 mg/day for 4–6 weeks (or other doses) with gradual
reduction can also accelerate the conversion of fulminate
disease course to common inflammatory acne [54, 73].
In contrast, oral non-steroidal anti-inflammatory
agents have rarely been administered in the treatment of
severe inflammatory acne forms.
Acne tarda
Systemic corticosteroids inhibit adrenal androgen liberation and, therefore, they are indicated in acne patients
with adrenal hyperandrogenism and increased dihydropiandrosterone levels, such as female patients with acne
tarda [74]. This variant of acne tarda is characterized by
inflammatory lesions, since increased dihydroepiandrosterone induces inflammation [75]. They are used at low
prednisone, prednisolone (2.5–7.5 mg/day prednisolone)
or dexamethasone doses [20] (fig. 6).
New Developments and Future Trends
After decades of stagnation, research on systemic acne
treatment has expanded markedly in the last several
years. The results of numerous studies have greatly increased our understanding of both the pathophysiology of
the disease and the mechanisms of action for current therapies. New developments occurred including the low-dose
long-term isotretinoin regimen, new isotretinoin formulations, understanding of isotretinoin’s anti-sebotropic action, new antibiotics, and combination treatments to
reduce toxicity and bacterial resistance, and new oral contraceptives. Future trends represent new anti-inflammatory agents, such as 5-lipoxygenase inhibitors, insulin-sen-
Zouboulis/Piquero-Martin
sitizing agents, 5·-reductase type 1 inhibitors, and antisense molecules.
Low-Dose Isotretinoin
Low-dose isotretinoin (0.1–0.3 mg/ml/day daily or intermittent use) can effectively control acne, also being
cost-effective. Nevertheless, the daily dose is too low for
the cumulative dose obtained to be definitively curative.
Although studies have been centered on the use of low
doses only in older patients with exceptionally oily skin or
in patients with long duration acne [76–80], there is a
trend by practicing dermatologists to use low-dose isotretinoin in adolescent acne with a tendency to become
inflammatory or in moderate acne as replacement of systemic antibiotics. The suggested rationale of such use is
the effective control of inflammation with the final objective of preventing inflammation and the resulting scars.
The approach taken is that of control and not of absolute
resolution, since this resolution will occur in the majority
of patients naturally. The simultaneous use of an effective
topical therapy is mandatory. Since a large percentage of
patients to be treated with mini-doses are women, they
should be made to understand that the teratogenesis risk
is the same as with the complete dose. Adverse events
with these low doses are almost absent.
New Isotretinoin Formulations
A recent study by Strauss et al. [81] using a micronized
isotretinoin formulation with higher bioavailability exhibited similar efficacy results of a single daily 0.4 mg/kg
dose of micronized isotretinoin and 1.0 mg/kg standard
isotretinoin administered in two divided doses after 20
weeks of treatment. Micronized isotretinoin presented a
safety profile similar to that of standard isotretinoin with
a lower risk of mucocutaneous adverse events and hypertriglyceridemia [82].
Understanding the Unique Activity of Isotretinoin
The high anti-sebotropic activity of isotretinoin is particularly surprising because of the fact that it has low binding affinities for both cellular retinoic acid-binding proteins I and II as well as for nuclear retinoic acid receptors
[83, 84]. Because retinoids are thought to exert most of
their effects by modulating gene expression and/or activating nuclear retinoid receptors, it has been suggested
that isotretinoin may act as a pro-drug that becomes
active after isomerization to tretinoin acid or conversion
to alitretinoin [84]. Indeed, current results reported by
Tsukada et al. [85] have shown that isotretinoin undergoes significant isomerization to tretinoin in cultured
Systemic Acne Treatment
sebocytes, an effect being specific for these cells. In addition, administration of isotretinoin to sebocytes only led
to a delayed induction of the cytochrome P450 isoenzymes responsible for tretinoin inactivation. Isotretinoin
effects were found to be dependent on the extra-cellular
albumin concentration [86]. On the other hand, tretinoin
acted via retinoic acid receptors (RAR) to exert its antiproliferative effect on sebocytes. Therefore, the molecular
basis for this anti-sebotrophic activity is probably a
selective intracellular isomerization of isotretinoin to tretinoin in human sebocytes, with isotretinoin representing
a pro-drug for tretinoin in this specific tissue. Newer data
indicate that isotretinoin metabolites, such as 4-oxo-isotretinoin, may also represent compounds exhibiting direct
anti-acne activity.
In addition to the better understanding of isotretinoin
activity, new possible adverse events have emerged. The
proposed relationship between the compound and depression as well as suicide was reviewed not to be based on a
putative molecular mechanism of the compound indicating that there is no evidence to support a casual connection [87]. On the other hand, 38 different signs and symptoms of ocular abnormalities were reported as ‘certain’ to
have resulted from the use of isotretinoin, among them
decreased dark adaptation may jeopardize adolescents
under the drug who drive in the night [88].
New Antibiotics
Limecycline is a second-generation tetracycline linked
to the amino acid lysine, with an efficacy similar to that of
doxycycline and minocycline [89]. It is used at a 300 mg
initial dose that is lowered to 150 mg after 2 weeks. It
exhibits excellent tolerance with scarce risk of hyperpigmentation, vestibular disorders and photosensitivity, and
can be administered together with food.
Roxithromycin, a macrolide antibiotic, is administered in a dose of 150 mg twice daily in the treatment of
inflammatory acne. It accumulates at therapeutic levels in
the pilosebaceous system [90] and exhibits an interesting
spectrum of effects, namely direct anti-inflammatory and
anti-androgenic activities. It significantly inhibits the production of lipase and neutrophil chemotactic factor by P.
acnes as well as of P. acnes-induced NF-kB activation at
concentrations much lower than the MIC at which the
growth curve of P. acnes is not affected [34, 91]. In addition, roxithromycin was found to serve as anti-androgen
only in the hypersensitive state to androgens, but not in
the physiological state through modulating end-organ hypersensitive condition to androgens [92].
Dermatology 2003;206:37–53
47
Azithromycin, another macrolide antibiotic, was
found as effective as doxycycline (100 mg/day) administered in a dose of 500 mg once a day for 4 days per month
for a total of 12 weeks on a pure protocol basis and statistically significantly better than doxycycline by intention to
treat analysis [93].
In an open study, levofloxacin was found effective for
inflammatory acne and achieved high levels in the lesions
[94].
Combination Treatments
Combinations of a topical retinoid (adapalene, tretinoin) or azelaic acid with oral antibacterial agents are recommended to induce maximum anti-inflammatory effect
in mild to moderate inflammatory acne [45, 46, 93, 95].
Such combinations can lead to a rapid dose reduction and
quicker discontinuation of oral antibiotics increasing the
effectiveness, improving the compliance, and reducing
the development of bacterial resistance to antibiotics.
New Oral Contraceptives
When oral contraceptives are administered in the
treatment of acne, it is possible that some women are
more sensitive to the androgenic effects of a progestin, but
it is more likely that the effect of progestin may be offset
by the estrogen. Although some progestins might be more
androgenic than others, all oral contraceptives, regardless
of the type of progestin each contains, increase SHBG and
inhibit serum androgen levels. This is also possible with
the marketed combination of ethinyl estradiol (20 Ìg) and
levonorgestrel (100 Ìg; one of the older and most androgenic progestins) found to produce a significant decrease
in comedones, as well as in papules and pustules [66, 96,
97].
The concentrations of estrogen in oral contraceptives
have decreased over the years from 150 to 35 Ìg, and in
the most recent forms to 20 Ìg, in order to reduce the side
effects of estrogen. On the other hand, many progestins
have been developed over the years and the third-generation progestins, including desogestrel, drospirenone, gestodene, and norgestimate, are more selective for the progesterone receptor rather than the androgen receptor. The
combinations of ethinyl estradiol (30–40 mg) and desogestrel (25–125 Ìg) [65, 98], ethinyl estradiol (20–35 Ìg)
and norethindrone acetate (1 g) [99], ethinyl estradiol
(30 mg) and drospirenone (3 mg) [64], and ethinyl estradiol and norgestimate (180–250 Ìg) [100, 101] have been
marketed as contraceptive pills; among them those including norethindrone acetate and norgestimate have
been approved for acne [27].
48
Dermatology 2003;206:37–53
New Anti-Inflammatory Agents
It is widely accepted that inflammation in acne vulgaris may be mainly induced by an immunologic reaction to
extracellular products of P. acnes [102]. However, it is by
no means clear that either bacteria or their products initiate follicular inflammation. Ingham et al. [103] investigated the presence of pro-inflammatory cytokines in open
acne comedones from untreated acne patients and found
bioactive interleukin(IL)-1·-like material. The majority
of open comedones also contained micro-organisms, but
there was no significant correlation between levels of any
cytokine, in particular IL-1·, and numbers of microorganisms.
Additional results have shown that the sebaceous gland
expresses a number of different cytokines at steady state,
without the influence of any external factors. Antilla et al.
[104] showed that IL-1 is present in normal sebaceous
glands and Boehm et al. [105] used in situ hybridization
techniques to show that messenger RNA (mRNA) for IL1·, IL-1ß and tumor necrosis factor-· is present at multiple sites in normal skin including the sebaceous glands.
Thus, while the presence of bacteria, most notably P.
acnes, may stimulate upregulation of cytokine expression
in sebaceous glands [106], pro-inflammatory cytokines
are expressed in these tissues in the absence of defined
external influences.
Guy et al. [107] assessed the action of IL-1· in the
microdissected human pilosebaceous infundibulum preparations in vitro and found an IL-1·-specific induction of
hypercornification of the infundibulum similar to that
seen in comedones. Follicular keratinocytes and sebocytes
in vitro were also found to produce pro-inflammatory
cytokines and chemokines [108]. Currently, inflammation has been suggested to occur due to enhancement of
IL-8 production in human monocytes and sebocytes
through a mechanism requiring transcription factor NFkB activation [34, 108] and involvement of Toll-like
receptor 2 [109, 110]. These results provide logical support for the use of anti-inflammatory regimens in the
treatment of acne [13].
The use of anti-inflammatory drugs for the treatment
of acne is further supported by recent results indicating a
key role for leukotriene B4 (LTB4) in the development of
tissue inflammation [111]. LTB4 is a pro-inflammatory
mediator synthesized from arachidonic acid. Synthesis of
LTB4 is catalyzed by 5-lipoxygenase and leukotriene A4
hydrolase and is increased by inflammatory mediators
including endotoxin, complement fragments, tumor necrosis factor-· and interleukins. LTB4 induces recruitment and activation of neutrophils, monocytes and eosin-
Zouboulis/Piquero-Martin
Fig. 7. The cascade of eicosanoid synthesis in the skin, as inflammatory signaling pathway possibly involved in the
development of acne lesions. IL-1ß = Interleukin-1ß; TNF-· = tumor necrosis factor-·; LTB4 = leukotriene B4;
15-HETE = 15-hydroxyeicosatetraenoic acid; PPAR = peroxisome proliferator-activated receptor [from ref. 24].
ophils. It also stimulates the production of a number of
pro-inflammatory cytokines and mediators that augment
and prolong tissue inflammation (fig. 7). Limited data
from pharmacological inhibition studies support a role for
LTB4 in the pathogenesis of neutrophil-mediated tissue
damage.
The potential importance of this inflammatory pathway for acne treatment was evaluated in a small cohort of
patients [112]. A 3-month study of the effectiveness of a
specific lipoxygenase inhibitor was performed by systemic administration in 10 patients with inflammatory
acne. Clinical evaluation of these patients indicated an
approximately 60% decrease in the acne severity index
within 3 weeks of the initiation of treatment and a 70%
reduction in inflammatory lesions at 3 months. Additional evaluation indicated an approximately 65% reduction
in total sebum lipids as well as a substantial decrease in
lipoperoxides. Free fatty acids were also decreased by
almost 80%. Bivariate analysis indicated that the decrease
in total sebum lipids, and especially in pro-inflammatory
lipids, was directly correlated with the improvement in
inflammatory lesions. Thus, the results of this small-scale
clinical trial and associated laboratory analysis strongly
support the conclusion that appropriate anti-inflammatory therapy has the potential to effectively treat acne.
These results also support the view that sebum lipids
induce inflammation in acne, independent of the presence of bacteria or increased systemic levels of proinflammatory molecules.
Eleven years ago, Wozel et al. [113] assessed the ability
of isotretinoin as well as a number of other agents to
inhibit transdermal migration of polymorphonuclear leukocytes stimulated by LTB4. Topical treatment with isotretinoin resulted in a marked and statistically significant
inhibition of the LTB4-induced migration of polymorphonuclear leukocytes. Retinoids are nowadays considered to regulate inflammation [114, 115] probably also
using the Toll-like receptor 2 pathway [116].
Systemic Acne Treatment
Dermatology 2003;206:37–53
Insulin-Sensitizing Agents
Since insulin has a direct effect on ovarian androgen
production in vitro, insulin resistance may play a crucial
49
role in the physiopathology of peripheral hyperandrogenism, including acne [117]. Insulin-sensitizing agents
have recently been investigated for their role in the short
term treatment of insulin resistance in polycystic ovary
syndrome. Controlled studies have shown that metformin
administration, by promoting body weight loss, can decrease fasting and stimulated plasma insulin levels. However, other studies have shown metformin 500 mg 3!
daily to decrease insulin secretion and to reduce ovarian
production of 17·-hydroxyprogesterone with recovery of
spontaneous or clomifene-induced ovulation, independently of weight loss. These findings suggest a new indication for metformin and present insulin-sensitizing agents
as a novel approach in the treatment of ovarian hyperandrogenism.
Peroxisomes play an important role in regulating cellular proliferation and differentiation as well as in the modulation of inflammatory mediators. In addition, peroxisomes have broad effects on the metabolism of lipids, hormones, and xenobiotics [118]. On the other hand, activation of peroxisome proliferator-activated receptor
(PPAR)-Á and -· by their respective specific ligands, thiazolidinedione and clofibrates, was found to induce lipid
droplet formation in rat preputial gland cells (resembling
sebocytes) but not epidermal cells in vitro [119]. PPAR-Á1
mRNA was also demonstrated in rat preputial gland cells
but not in epidermal cells. These findings are compatible
with the concepts that PPAR-Á1 gene expression plays a
unique role in the differentiation of sebocyte-like cells.
These findings have implications for the development of
new modalities of treatment for acne vulgaris and explain
why lipoxygenase inhibitors inhibit lipid synthesis [112]:
The lipoxygenase products LTB4 and 15-HETE are natural ligands of PPAR-· and PPAR-Á, respectively.
reductase 1 inhibitors seem the ideal drugs for treatment
of acne and hirsutism [121–123] and have been introduced in clinical studies [27].
Antisense Molecules
The androgen receptor is involved in the development
of acne and its expression can classically be regulated by
androgen receptor blockers. A more elegant way is the
transient transfection of skin cells with antisense oligonucleotides against the androgen receptor [124]. The development of thioat- and ribosyl-antisense oligonucleotides
against the androgen receptor led with high specificity in a
transient diminished protein expression of the receptor
and to a strong inhibition of the biological activity of
androgens in human sebocytes and keratinocytes in vitro.
Such experiments are only in an initial phase. The future
clinical use of such highly specific compounds is dependent on several factors, among them being the effective
administration pathway and the kind of transfection systems to be applied.
Conclusion
Despite the interest on the development of topical
treatments for acne in the last decades [30], systemic
treatment is still a milestone, especially in the treatment
of moderate-to-severe scarring types of the disease. The
establishment of new systemic drugs for acne is based on
the consideration of successes and pitfalls of the past and
the emerging knowledge of the future [125]. Among all
pathogenetic factors of acne, inflammation seems to be
rediscovered [13] and anti-inflammatory concepts seem
to become the new trend of systemic and topical acne
treatment.
5·-Reductase Type 1 Inhibitors
The inhibitors of 5·-reductase isoenzymes (1 and 2)
can be schematically divided in three groups according
they substrate specificity: Pure or preferential inhibitors
of 5·-reductase 1, pure or preferential inhibitors of 5·reductase 2, and dual inhibitors [26, 120]. Despite the fact
that several steroidal and non-steroidal inhibitors have
been synthesized and experimented in pharmacological
models, only finasteride has been extensively used for
clinical purposes, namely benign prostate hyperplasia and
male baldness with positive results. In women, finasteride
has been used in some control trials for treatment of hirsutism with an objective favorable response. On the basis of
experimental observations on distribution of 1 and 2 isoenzymes in human skin, scalp and prostate, the pure 5·-
50
Dermatology 2003;206:37–53
Zouboulis/Piquero-Martin
References
1 Gollnick H, Zouboulis ChC, Akamatsu H, Kurokawa I, Schulte A: Pathogenesis and pathogenesis related treatment of acne. J Dermatol
1991;18:489–499.
2 Brown SK, Shalita AR: Acne vulgaris. Lancet
1998;351:1871–1876.
3 Zouboulis ChC: Acne: Current aspects on pathology and treatment. Dermatol Experiences
1999;1:6–37.
4 Piquero-Martı´n J: Acné – Manejo racional, ed
3. Caracas, Corpogra´fica, 2000.
5 Cunliffe WJ, Eady EA: A reappraisal and update on the pathogenesis and treatment of acne.
Cur Opin Infect Dis 1992;5:703–710.
6 Dreno B, Poli F: Epidemiology of acne. Dermatology 2003;206:7–10.
7 Stern R: Medication and medical service utilization for acne 1995–1998. J Am Acad Dermatol 2000;43:1042–1048.
8 Leyden JJ: Therapy for acne vulgaris. N Engl J
Med 1997;336:1156–1162.
9 Green J, Sinclair RD: Perceptions of acne vulgaris in final year medical student written examination answers. Austr J Dermatol 2001;42:
98–101.
10 Zouboulis ChC, Fimmel S, Ortmann J, Turnbull JR, Boschnakow A: Sebaceous glands; in
Hoath SB, Maibach H (eds): Neonatal Skin –
Structure and Function, ed 2. New York, Marcel Dekker, in press.
11 Cunliffe WJ, Holland DB, Clark SM, Stables
GI: Comedogenesis: Some new aetiological,
clinical and therapeutic strategies. Dermatology 2003;206:11–16.
12 Eady EA, Gloor M, Leyden JJ: Propionibacterium acnes resistance: A world wide problem.
Dermatology 2003;206:54–56.
13 Zouboulis ChC: Is acne vulgaris a genuine
inflammatory disease? Dermatology 2001;203:
277–279.
14 Herane MI, Ando I: Acne in infancy and acne
genetics. Dermatology 2003;206:24–28.
15 Zouboulis ChC, Seltmann H, Hiroi N, Chen
W, Young M, Oeff M, Scherbaum WA, Orfanos CE, McCann SM, Bornstein SR: Corticotropin releasing hormone: An autocrine hormone that promotes lipogenesis in human sebocytes. Proc Natl Acad Sci USA 2002;99:
7148–7153.
16 Toyoda M, Morohashi M: New aspects in acne
inflammation. Dermatology 2003;206:17–23.
17 O’Brien SC, Lewis JB, Cunliffe WJ: The Leeds
revised acne grading system. J Dermatol Treat
1998;9:215–220.
18 Pochi PE, Shalita AR, Strauss JS, Webster SB,
Cunliffe WJ, Katz HI, Kligman AM, Leyden
JJ, Lookingbill DP, Plewig G, et al: Report of
the consensus conference on acne classification. J Am Acad Dermatol 1991;24:495–500.
19 Cunliffe WJ, van de Kerkhof PC, Caputo R,
Cavicchini S, Cooper A, Fyrand OL, Gollnick
H, Layton AM, Leyden JJ, Mascaro JM, Ortonne JP, Shalita A: Roaccutane treatment
guidelines: Results of an international survey.
Dermatology 1997;194:351–357.
Systemic Acne Treatment
20 Orfanos CE, Adler YD, Zouboulis ChC: The
SAHA syndrome. Horm Res 2000;54:251–
258.
21 Thiboutot DM: Endocrinological evaluation
and hormonal therapy for women with difficult
acne. J Eur Acad Dermatol Venereol 2001;
15(suppl 3):57–61.
22 Madden WS, Landells ID, Poulin Y, Searles
GE, Smith KC, Tan JK, Toole J, Zip CM,
Degreef H: Treatment of acne vulgaris and prevention of acne scarring: Canadian consensus
guidelines. J Cutan Med Surg 2000;4(suppl 1):
S2–13.
23 Slayden SM, Moran C, Sams WM Jr, Boots LR,
Azziz R: Hyperandrogenemia in patients presenting with acne. Fertil Steril 2001;75:889–
892.
24 Zouboulis ChC: Human skin: An independent
peripheral endocrine organ. Horm Res 2000;
54:230–242.
25 Thiboutot D, Chen W: Update and future of
hormonal therapy in acne. Dermatology 2003;
206:56–67.
26 Chen W, Thiboutot D, Zouboulis ChC: Cutaneous androgen metabolism: Basic research
and clinical perspectives. J Invest Dermatol, in
press.
27 Shaw JC: Hormonal therapies in acne. Expert
Opin Pharmacother 2002;3:865–874.
28 Orfanos CE, Zouboulis ChC: Oral retinoids in
the treatment of seborrhoea and acne. Dermatology 1998;196:140–147.
29 Zouboulis ChC, Korge B, Akamatsu H, Xia L,
Schiller S, Gollnick H, Orfanos CE: Effects of
13-cis-retinoic acid, all-trans-retinoic acid and
acitretin on the proliferation, lipid synthesis
and keratin expression of cultured human sebocytes in vitro. J Invest Dermatol 1991;96:
792–797.
30 Gollnick H: Topical treatment in acne: Current
status and future aspects. Dermatology 2003;
206:29–36.
31 Kaminsky A: Less common methods to treat
acne. Dermatology 2003;206:68–73.
32 Toyoda M, Morohashi M: An overview of topical antibiotics for acne treatment. Dermatology
1998;196:130–134.
33 Meynadier J, Alirezai M: Systemic antibiotics
for acne. Dermatology 1998;196:135–139.
34 Chen Q, Koga T, Uchi H, Hara H, Terao H,
Moroi Y, Urabe K, Furue M: Propionibacterium acnes-induced IL-8 production may be
mediated by NF-kappaB activation in human
monocytes. J Dermatol Sci 2002;29:97–103.
35 Sykes NL Jr, Webster GF: Acne. A review of
optimum treatment. Drugs 1994;48:59–70.
36 Holland KT, Aldana O, Bojar RA, Cunliffe
WJ, Eady EA, Holland DB, Ingham E,
McGeown C, Till A, Walters C: Propionibacterium acnes and acne. Dermatology 1998;196:
67–68.
37 Akamatsu H, Tomita T, Horio T: Effects of
roxithromycin on the production of lipase and
neutrophil chemotactic factor by Propionibacterium acnes. Dermatology 2002;204:277–
280.
38 Leyden JJ: Current issues in antimicrobial
therapy for the treatment of acne. J Eur Acad
Dermatol Venereol 2001;15(suppl 3):51–55.
39 Chosidow O, Poli F, Naline E, Advenier C,
Revuz J: Comedonal diffusion of minocycline
in acne. Dermatology 1998;196:162.
40 Colvin JH, Sheth AP: Minocycline hypersensitivity syndrome with hypotension mimicking
septic shock. Pediatr Dermatol 2001;18:295–
298.
41 Kiessling S, Forrest K, Moscow J, Gewirtz A,
Jackson E, Roszman T, Goebel J: Interstitial
nephritis, hepatic failure, and systemic eosinophilia after minocycline treatment. Am J Kidney Dis 2001;38:E36.
42 Seaman HE, Lawrenson RA, Williams TJ, MacRae KD, Farmer RD: The risk of liver damage
associated with minocycline: A comparative
study. J Clin Pharmacol 2001;41:852–860.
43 Balestrero S, Ciambellotti A, Parodi A, Rebora
A: Minocycline-induced lupus-like syndrome.
Int J Dermatol 2001;40:474–475.
44 Hughes BR, Murphy C, Barnett J, Cunliffe WJ:
Strategy of acne therapy with long-term antibiotics. Br J Dermatol 1989;121:623–628.
45 Berson DS, Shalita AR: The treatment of acne:
The role of combination therapies. J Am Acad
Dermatol 1995;32:S31–S41.
46 Gollnick HP, Graupe K, Zaumseil RP: Comparison of combined azelaic acid cream plus
oral minocycline with oral isotretinoin in severe acne. Eur J Dermatol 2001;11:538–544.
47 Strauss JS, Rapini RP, Shalita AR, Konecky E,
Pochi PE, Comite H, Exner JH: Isotretinoin
therapy for acne: Results of a multicenter doseresponse study. J Am Acad Dermatol 1984;10:
490–496.
48 Layton AM, Knaggs H, Taylor J, Cunliffe WJ:
Isotretinoin for acne vulgaris –10 years later: A
safe and successful treatment. Br J Dermatol
1993;129:292–296.
49 Lehucher-Cheyrac DS, Weber-Buisset MJ: Isotretinoin and acne in practice: A prospective
analysis of 188 cases over 9 years. Dermatology
1993;186:123–128.
50 Piquero Martı´n J, Urdaneta N: Experiencia
clı´nica del Isotretinoı´n en acné, Rosa´cea e Hidradenitis. Derm Venez 1987;25:35–40.
51 Leyden JJ, McGinley KJ, Foglia AN: Qualitative and quantitative changes in cutaneous bacteria associated with systemic isotretinoin therapy for acne conglobata. J Invest Dermatol
1986;86:390–393.
52 Chivot M, Midoun H: Isotretinoin and acne: A
study of relapses. Dermatologica 1990;180:
240–243.
53 Stainforth JM, Layton AM, Taylor JP, Cunliffe
WJ: Isotretinoin for the treatment of acne vulgaris: Which factors may predict the need for
more than one course? Br J Dermatol 1993;
129:297–301.
54 Karvonen SJ: Acne fulminans. Report of clinical findings and treatment of twenty-four patients. J Am Acad Dermatol 1993;28:572–579.
Dermatology 2003;206:37–53
51
55 Cunliffe WJ, Layton AM: Oral isotretinoin: Patient selection and management. J Dermatol
Treat 1993;4(suppl 2):S10–S15.
56 Dai WS, LaBraico JM, Stern RS: Epidemiology
of isotretinoin exposure during pregnancy. J
Am Acad Dermatol 1992;26:599–606.
57 Mitchell AA, Van Bennekom CM, Louik C: A
pregnancy-prevention program in women of
childbearing age receiving isotretinoin. N Engl
J Med 1995;333:101–106.
58 Altman RS, Altman LJ, Altman JS: A proposed
set of new guidelines for routine blood tests
during isotretinoin therapy for acne vulgaris.
Dermatology 2002;204:232–235.
59 Margolis DJ, Attie M, Leyden JJ: Effects of isotretinoin on bone mineralization during routine therapy with isotretinoin for acne vulgaris.
Arch Dermatol 1996;132:769–774.
60 Shaw JC: Antiandrogen and hormonal treatment of acne. Dermatol Clin 1996;4:803–811.
61 Beylot C, Doutre MS, Beylot-Barry M: Oral
contraceptives and cyproterone acetate in female acne treatment. Dermatology 1998;196:
148–152.
62 Piquero Martin J, Acosta H: Uso de acetato de
ciproterona en el tratamiento del acné. Med
Cutan Ibero Lat Am 1982;10:261–266.
63 Carmina E, Lobo RA: A comparison of the relative efficacy of antiandrogens for the treatment of acne in hyperandrogenic women. Clin
Endocrinol (Oxf) 2002;57:231–234.
64 van Vloten WA, van Haselen CW, van Zuuren
EJ, Gerlinger C, Heithecker R: The effect of 2
combined oral contraceptives containing either
drospirenone or cyproterone acetate on acne
and seborrhea. Cutis 2002;69(suppl):2–15.
65 Vartiainen M, de Gezelle H, Broekmeulen CJ:
Comparison of the effect on acne with a combiphasic desogestrel-containing oral contraceptive and a preparation containing cyproterone
acetate. Eur J Contracept Reprod Health Care
2001;6:46–53.
66 Worret I, Arp W, Zahradnik HP, Andreas JO,
Binder N: Acne resolution rates: results of a
single-blind, randomized, controlled, parallel
phase III trial with EE/CMA (Belara) and EE/
LNG (Microgynon). Dermatology 2001;203:
38–44.
67 Thiboutot D: Acne and rosacea: New and
emerging therapies. Dermatol Clin 2000;18:
63–71.
68 Brache V, Faundes A, Alvarez F, Cochon L:
Nonmenstrual adverse events during use of implantable contraceptives for women: Data from
clinical trials. Contraception 2002;65:63–74.
69 Lubbos HG, Hasinski S, Rose LI, Pollock J:
Adverse effects of spironolactone therapy in
women with acne. Arch Dermatol 1998;134:
1162–1163.
70 Schmidt JB: Other antiandrogens. Dermatology 1998;196:153–157.
71 Dodin S, Faure N, Cedrin I, Mechain C, Turcot-Lemay L, Guy J, Lemay A: Clinical efficacy
and safety of low-dose flutamide alone and
combined with an oral contraceptive for the
treatment of idiopathic hirsutism. Clin Endocrinol (Oxf) 1995;43:578–582.
52
72 Seukeran DC, Cunliffe WJ: The treatment of
acne fulminans: A review of 25 cases. Br J Dermatol 1999;141:307–309.
73 Bass D, Zouboulis ChC: Behandlung der Acne
fulminans mit Isotretinoin und Prednisolon. Z
Hautkr 2001;76:473.
74 Vexiau P, Baspeyras M, Chaspoux C, Foin N,
Allaert FA, Abramovici Y: Acne in adult women: data from a national study on the relationship between type of acne and markers of clinical hyperandrogenism. Ann Dermatol Venereol 2002;129:174–178.
75 Bradlow HL, Murphy J, Byrne JJ: Immunological properties of dehydroepiandrosterone, its
conjugates, and metabolites. Ann NY Acad Sci
1999;876:91–101.
76 Honeyman J: Isotretinoı´na oral en dosis bajas
en el tratamiento del acné moderado. Dermatol
Argent 1998;4:338–344.
77 Goulden V, Clark SM, McGeown C, Cunliffe
WJ: Treatment of acne with intermittent isotretinoin. Br J Dermatol 1997;137:106–108.
78 Palmer RA, Sidhu S, Goodwin PG: ‘Microdose’ isotretinoin. Br J Dermatol 2000;143:
205–206.
79 Seukeran DC: Acne vulgaris in the elderly: The
response to low dose isotretinoin. Br J Dermatol 1998,139:99–101.
80 Piquero-Martin J, Misticone S, Piquero-Casals
V, Piquero-Casals J: Topic therapy-mini isotretinoin doses vs topic therapy-systemic antibiotics in the moderate acne patients. Ann Dermatol Venereol 2002;129:S382.
81 Strauss JS, Leyden JJ, Lucky AW, Lookingbill
DP, Drake LA, Hanifin JM, Lowe NJ, Jones
TM, Stewart DM, Jarratt MT, Katz I, Pariser
DM, Pariser RJ, Tschen E, Chalker DK, Rafal
ES, Savin RP, Roth HL, Chang LK, Baginski
DJ, Kempers S, McLane J, Eberhardt D, Leach
EE, Bryce G, Hong J: A randomized trial of the
efficacy of a new micronized formulation versus a standard formulation of isotretinoin in
patients with severe recalcitrant nodular acne.
J Am Acad Dermatol 2001;45:187–195.
82 Strauss JS, Leyden JJ, Lucky AW, Lookingbill
DP, Drake LA, Hanifin JM, Lowe NJ, Jones
TM, Stewart DM, Jarratt MT, Katz I, Pariser
DM, Pariser RJ, Tschen E, Chalker DK, Rafal
ES, Savin RP, Roth HL, Chang LK, Baginski
DJ, Kempers S, McLane J, Eberhardt D, Leach
EE, Bryce G, Hong J: Safety of a new micronized formulation of isotretinoin in patients
with severe recalcitrant nodular acne: A randomized trial comparing micronized isotretinoin with standard isotretinoin. J Am Acad
Dermatol 2001;45:196–207.
83 Allenby G, Bocquel MT, Saunders M, Kazmer
S, Speck J, Rosenberger M, Lovey A, Kastner
P, Grippo JF, Chambon P, et al: Retinoic acid
receptors and retinoid X receptors: Interactions with endogenous retinoic acids. Proc Natl
Acad Sci USA 1993;90:30–34.
84 Sitzmann JH, Bauer FW, Cunliffe WJ, Holland
DB, Lemotte PK: In situ 13-cis-hybridization
analysis of CRABP II expression in sebaceous
follicles from retinoic acid-treated acne patients. Br J Dermatol 1995;133:241–248.
Dermatology 2003;206:37–53
85 Tsukada M, Schröder M, Roos TC, Chandraratna RAS, Reichert U, Merk HF, Orfanos CE,
Zouboulis ChC: 13-cis Retinoic acid exerts its
specific activity on human sebocytes through
selective intracellular isomerization to all-trans
retinoic acid and binding to retinoid acid receptors. J Invest Dermatol 2000;115:321–327.
86 Tsukada M, Schröder M, Seltmann H, Orfanos
CE, Zouboulis ChC: High albumin levels restrict the kinetics of 13-cis retinoic acid uptake
and intracellular isomerization to all-trans retinoic acid and inhibit its anti-proliferative effect
on SZ95 sebocytes. J Invest Dermatol 2002;
119:182–185.
87 Jacobs DG, Deutsch NL, Brewer M: Suicide,
depression, and isotretinoin: Is there a causal
link? J Am Acad Dermatol 2001;45:S168S175.
88 Fraunfelder FT, Fraunfelder FW, Edwards R:
Ocular side effects possibly associated with isotretinoin usage. Am J Ophthalmol 2001;132:
299–305.
89 Pierard-Franchimont C, Goffin V, Arrese JE,
Martalo O, Braham C, Slachmuylders P, Pierard GE: Lymecycline and minocycline in inflammatory acne: A randomized, double-blind
intent-to-treat study on clinical and in vivo
antibacterial efficacy. Skin Pharmacol Appl
Skin Physiol 2002;15:112–119.
90 Akamatsu H, Horio T: Concentration of roxithromycin in the lesions of acne vulgaris. J Int
Med Res 2001;29:537–540.
91 Akamatsu H, Tomita T, Horio T: Effects of
roxithromycin on the production of lipase and
neutrophil chemotactic factor by Propionibacterium acnes. Dermatology 2002;204:277–
280.
92 Inui S, Nakajima T, Fukuzato Y, Fujimoto N,
Chang C, Yoshikawa K, Itami S: Potential antiandrogenic activity of roxithromycin in skin. J
Dermatol Sci 2001;27:147–151.
93 Parsad D, Pandhi R, Nagpal R, Negi KS: Azithromycin monthly pulse vs daily doxycycline
in the treatment of acne vulgaris. J Dermatol
2001;28:1–4.
94 Kawada A, Aragane Y, Tezuka T: Levofloxacin
is effective for inflammatory acne and achieves
high levels in the lesions: An open study. Dermatology 2002;204:301–302.
95 Soto P, Cunliffe W, Meynadier J, Alirezai M,
George S, Couttes I, Roseeuw D, Briantais P:
Efficacy and safety of combined treatment of
acne vulgaris with adapalane and lymecycline.
Ann Dermatol Venereol 2002;129:1S602.
96 Lemay A, Dewailly SD, Grenier R, Huard J:
Attenuation of mild hyperandrogenic activity
in postpubertal acne by a triphasic oral contraceptive containing low doses of ethynyl estradiol and d,l-norgestrel. J Clin Endocrinol Metabolism 1990;71:8–14.
97 Thiboutot D, Archer DF, Lemay A, Washenik
K, Roberts J, Harrison DD: A randomized,
controlled trial of a low-dose contraceptive
containing 20 microg of ethinyl estradiol and
100 microgram of levonorgestrel for acne treatment. Fertil Steril 2001;76:461–468.
Zouboulis/Piquero-Martin
98 Vree ML, Schmidt J: A large observational
clinical evaluation of a desogestrel-containing
combiphasic oral contraceptive in Germany.
Eur J Contracept Reprod Health Care 2001;6:
108–114.
99 Maloney M, Arbit D, Flack M, McLaughlinMiley C, Sevilla C, Derman R: Use of a lowdose oral contraceptive containing norethindrone acetate and ethinyl estradiol in the
treatment of moderate acne vulgaris. Clin J
Women’s Hlth 2001;1:124–131.
100 Lucky A, Henderson T, Olson W, Robisch D,
Lebwohl M, Swinyer L: Effectiveness of norgestimate and ethinyl estradiol in treating
moderate acne vulgaris. J Am Acad Dermatol
1997;37:746–754.
101 Redmond GP, Olson WH, Lippman JS,
Kafrissen ME, Jones TM, Jorizzo JL: Norgestimate and ethinyl estradiol in the treatment
of acne vulgaris: A randomized, placebo-controlled trial. Obstet Gynecol 1997;89:615–
622.
102 Burkhart CG, Cantrill J, Butcher CL, Lehmann PF. Propionibacterium acnes: Interaction with complement and development of an
enzyme-linked immunoassay for the detection of antibody. Int J Dermatol 1999;38:
200–203.
103 Ingham E, Eady EA, Goodwin CE, Cove JH,
Cunliffe WJ. Pro-inflammatory levels of interleukin-1 alpha-like bioactivity are present
in the majority of open comedones in acne
vulgaris. J Invest Dermatol 1992;98:895–
901.
104 Antilla HS, Reitamo S, Saurat JH: Interleukin
1 immunoreactivity in sebaceous glands. Br J
Dermatol 1992;127:585–588.
105 Boehm KD, Yun JK, Strohl KP, Elmets CA:
Messenger RNAs for the multifunctional cytokines interleukin-1 alpha, interleukin-1
beta and tumor necrosis factor-alpha are
present in adnexal tissues and in dermis of
normal human skin. Exp Dermatol 1995;4:
335–341.
Systemic Acne Treatment
106 Vowels BR, Yang S, Leyden JJ: Induction of
proinflammatory cytokines by a soluble factor of Propionibacterium acnes: Implications
for chronic inflammation acne. Infect Immun
1995;63:3158–3165.
107 Guy R, Green MR, Kealey T: Modeling acne
in vitro. J Invest Dermatol 1996;106:176–
182.
108 Seltmann H, Oeff M, Zouboulis ChC: CD14
expression in human sebocytes and IL8 regulation by lipopolysaccharides, phorbol myristate acetate and linoleic acid. Arch Dermatol
Res 2002;294:33.
109 Kim J, Ochoa MT, Krutzik SR, Takeuchi O,
Uematsu S, Legaspi AJ, Brightbill HD, Holland D, Cunliffe WJ, Akira S, Sieling PA,
Godowski PJ, Modlin RL: Activation of tolllike receptor 2 in acne triggers inflammatory
cytokine responses. J Immunol 2002;169:
1535–1541.
110 Oeff MK, Seltmann H, Hakiy N, Bogdanoff
B, Nastos A, Walters R, Bornstein SR, Zouboulis ChC: Toll-like receptor 2 and 4-dependent regulation of inflammatory signaling in
human sebocytes. J Invest Dermatol 2002;
119:736.
111 Crooks SW, Stockley RA: Leukotriene B4. Int
J Biochem Cell Biol 1998;30:173–178.
112 Zouboulis ChC: Exploration of retinoid activity and the role of inflammation in acne:
Issues affecting future directions for acne
therapy. J Eur Acad Dermatol Venereol 2001;
15(suppl 3):63–67.
113 Wozel G, Chang A, Zultak M, et al: The effect
of topical retinoids on the leukotriene-B4induced migration of polymorphonuclear leukocytes into human skin. Arch Dermatol Res
1991;283:158–161.
114 Berbis Ph: L’isotrétinoi¨ne est-elle pro ou antiinflammatoire? Ann Dermatol Venereol
2001;128:2S25–2S28.
115 Zouboulis ChC, Oeff KM, Seltmann H, Walters RJ, Nastos A, Bornstein SR: Differential
modulation of CD14 expression in sebocytes
by retinoids. Arch Dermatol Res 2002;294:
48.
116 Kang S: Current perspectives on acne inflammation and scarring. Ann Dermatol Venereol
2002;129:1S190.
117 Pugeat M, Ducluzeau PH: Insulin resistance,
polycystic ovary syndrome and metformin.
Drugs 1999;58(suppl 1):41–46; discussion
75–82.
118 Smith KJ, Dipreta E, Skelton H: Peroxisomes
in dermatology. Part I. J Cutan Med Surg
2001;5:231–243.
119 Rosenfield RL, Kentsis A, Deplewski D, Ciletti N: Rat preputial sebocyte differentiation
involves peroxisome proliferator-activated
receptors. J Invest Dermatol 1999;112:226–
232.
120 Chen W-C, Zouboulis ChC, Orfanos CE: The
5·-reductase system and its inhibitors; recent
development and its perspective in treating
androgen-dependent skin disorders. Dermatology 1996;193:177–184.
121 Cilotti A, Danza G, Serio M: Clinical application of 5alpha-reductase inhibitors. J Endocrinol Invest 2001;24:199–203.
122 Chen W, Zouboulis ChC, Fritsch M, BlumePeytavi U, Kodelja V, Goerdt S, Luu-The V,
Orfanos CE: Evidence of heterogeneity and
quantitative differences of the type 1 5·reductase expression in cultured human skin
cells: Evidence of its presence in melanocytes.
J Invest Dermatol 1998;110:84–89.
123 Fritsch M, Orfanos CE, Zouboulis ChC: Sebocytes are the key regulators of androgen
homeostasis in human skin. J Invest Dermatol 2001;116:793–800.
124 Fimmel S, Saborowski A, Bogdanoff B, Orfanos CE, Zouboulis ChC: Inhibition of androgen receptor expression and of androgen activity on human sebocytes by antisense oligonucleotides. Ann Dermatol Venereol 2002;
129:1S375.
125 Cunliffe WJ: Looking back to the future –
Acne. The first William J. Cunliffe Lecture.
Dermatology 2002;204:167–172.
Dermatology 2003;206:37–53
53